The long term objectives of the research training plan is to serve as a training vehicle for the development of critical and comprehensive research skills as a clinician scientist for Dr. Meeghan Lautner. Using a structured MS program in Clinical Investigation (MSCI) as a formal training vehicle, the proposed research plan will test the hypothesis that tumor cells release a soluble factor that activates or sensitizes the capsaicin receptor TRPV1. TRPV1 is expressed on a major subclass of nociceptors and appears to be pivotally involved in many pain states. Although several mechanisms for tumor-induced pain have been proposed, the proposed hypothesis provides a novel mechanism involving activation of the transient receptor subtype V1 (TRPV1). If the data generated supports this hypothesis, then completely new therapeutic interventions may be developed for the management of cancer pain. This project has clear medical and scientific implications. Despite decades of success in treating many forms of cancer, a continuing area of concern is pain associated with cancer, which is a well recognized major clinical problem for many patients (Mantyh 2006;Loscalzo et al. 2007;Macvean et al. 2007). Preliminary data generated to date provide strong support for the release of a soluble factor which triggers CGRP release from cultured sensory neurons via TRPV1, as indicated by blockade with the antagonist I-RTX. The first specific aim will determine whether ATTC tumor cell lines release a soluble factor that activates or sensitizes TRPV1 using both cell signaling (intracellular calcium accumulation, [Ca]i) and functional (calcitonin gene-related peptide, CGRP release) assays on cultured sensory neurons. The second aim will determine whether tumors collected during surgical de-bulking procedures from patients release a soluble factor that activates or sensitizes TRPV1 and whether tumors that release this soluble compound are associated with patients reporting greater pain intensities compared with tumors collected from other patients that do not release a TRPV1 modulating factor. PUBLIC HEALTH RELEVANCE: Despite considerable advances over the last several decades, cancer pain represents a major problem in many patients. This project will evaluate whether the capsaicin receptor, TRPV1, contributes to cancer pain. If so, then new types of pain killers might be of value to future patients.